CoEE Endowed Chair Bennett publishes major drug safety study revealing industry and academic researchers reached different conclusions about ESAs and tumor growth; authors call for research standardization to protect patients.
FOR IMMEDIATE RELEASE
September 13, 2010
NOTE: For support materials including author bios, topic backgrounders, and photos, please go to http://www.sccoee.org/esasarticle.htm.
A team of investigators led by a physician-scientist at the South Carolina College of Pharmacy's Center of Economic Excellence (CoEE) for Medication Safety and Efficacy has shown differences in methodology and results from privately- and publicly-funded studies, indicating a need for greater collaboration between the sectors. The study is published as the lead article in the September 13 edition of the journal Archives of Internal Medicine.
The study "Association Between Pharmaceutical Support and Basic Science Research on Erythropoiesis-Stimulating Agents (ESAs)" showed researchers without pharmaceutical industry support are more likely than those with support to identify detrimental in vitro effects of ESAs, including potentially harmful effects on cancer patients.
"The study shows that differences in methodology and results from privately- and publicly-funded studies is a clarion call for greater collaboration between the sectors," said lead author Charles Bennett, endowed chair of the CoEE for Medication Safety and Efficacy (CMSE) at the South Carolina College of Pharmacy (SCCP). "If good scientists in both arenas are coming up with strikingly different results, it lowers the return on investment in the funding for both. Ultimately, that decreases positive outcomes for the company, the profession, and the patient."
Clinicians prescribe ESAs, a form of the human protein erythopoitetin that stimulates bone marrow to manufacture red blood cells, to treat anemia, which can result from chemotherapy or from kidney failure. Since 1993, ESAs have been marketed for cancer patients. These agents, marketed as Procrit by Johnson and Johnson and Aranesp by AMGEN, now bear "black-box" warnings on their labels stating they can increase the risk for death in cancer patients. Before a cancer patient receives any dose of an ESA, he/she must sign an informed consent document stating that the drug can increase their risk of death. Also, earlier this year, the manufacturers now require that oncologists treating cancer patients with ESAs must complete special training every three years and discuss drug-risk information with patients.
"This paper addresses the 800 pound gorilla for ESAs--is there basic science data showing that these drugs can cause tumor cells to grow?" said Bennett. "The study showed there was difference in pharma-funded and non pharma-funded studies. The study did not show who was right or wrong. The science is complicated. Essentially there are three areas--agreement on controls, agreement on the antibodies, definition of cell growth--about which lack of standardization leads to uncertainty. Public and private researchers need to come to a consensus so there is adjudication on the study standards."
Bennett plans to form a public-private steering committee at the CoEE for Medication Safety and Efficacy at the South Carolina College of Pharmacy to look at best practices in study methodology and protocols. "Hundreds of millions of dollars and thousands of lives depend on it," he said.
Method and Results
The researchers analyzed 827 total articles and excluded 758 based on a variety of disqualifying criteria. Seventy-four studies were evaluated in the final analysis, including 64 investigations from investigators without funding from ESA manufacturers (no pharma funding), seven from academic investigators with pharma funding (pharma funded researchers), and three from investigators with employment by ESA manufacturers (pharma employees). The research team found investigations without pharma funding were more likely than pharma-funded researchers and pharma employees to report:
* EpoRs on solid tumor cells (100 percent, 60 percent, 67 percent)
* erythropoietin (Epo) induced signaling events (94 percent, 0 percent, 0 percent)
* changes in cellular function (57 percent, 0 percent, 0 percent)
Investigators without pharma funding also drew conclusions less favorable than others. Qualitative statements on potential clinical relevance were included in 42 of their studies, five from pharma- funded researchers' studies and two studies reported by pharma employees. These statements were similarly at odds:
* investigations had identified potentially harmful effects of Epo on cancer cells (57 percent, 0 percent, 0 percent)
* investigations had identified potentially beneficial antitumor effects (14 percent, 60 percent, 0 percent)
Conclusions and Recommendations
The authors conclude that policies are needed to help alleviate conflict of interest concerns even in the basic science setting. Beginning in 2012 and reporting in 2013, all pharmaceutical manufacturers will be required to disclose certain physician-payment information as part of the 2010 Patient Protection and Affordable Care Act (PPACA). The authors suggest it should not stop there.
"Basic science researchers may face similar challenges with regard to conflict of interest as physicians," said co-author Stephen Lai, M.D., Ph.D., associate professor of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center. "Clinical researchers have certain protocols they follow to protect against conflicts of interest and the outcome of this study suggests that basic science research would benefit from those same systems."
In addition, the conflicts of interest would benefit from policies of transparency.
"Conflicts of interest in the basic and clinical sciences may alter the reporting of results," said co-author Oliver Sartor, C.E. and Bernadine Laborde Professor of Cancer Research, Tulane University School of Medicine, and medical director of the Tulane Cancer Center in New Orleans. "The process of declaring conflicts of interest for basic scientists needs to be examined very carefully going forward, and policies should be considered to ensure that these conflicts are apparent to all."
The authors' recommendations include:
* extending the PPACA to include reporting by basic science researchers
* making nonclinical basic science researchers follow the same policies that clinical researchers follow, including disclosure of funding sources in communications with research institutions, journal editors and publications
* making manufacturers produce reports on certain basic science questions within pre-agreed-on periods after regulatory approval for a clinical indication is granted
About the Authors
Charles Bennett is the CoEE Endowed Chair in Medication Safety and Efficacy at the South Carolina College of Pharmacy and director of the Southern Network on Adverse Reactions (SONAR) in Columbia, S.C. Stephen Lai is an Associate Professor of the Department of Head and Neck Surgery, University o f Texas, M. D. Anderson Cancer Center in Houston. Michael Henke is a Professor of Radiation Oncology, University Hospital in Freiburg, Germany and the principal investigator of the first clinical trial that identified increased mortality risks when cancer patients received ESAs. Sara Barnato was a post-doctoral fellow at the Center for Management of Complex Chronic Care at the Chicago VA Medical Center. James Armitage is a Professor of Hematology and Oncology at the University of Nebraska School of Medicine, in Omaha, and a former president of the American Society of Clinical Oncology. Oliver Sartor is the C.E. and Bernadine Laborde Professor of Cancer Research, Tulane University School of Medicine, and Medical Director of the Tulane Cancer Center in New Orleans
About the Center for Medication Safety and Efficacy
The Medication Safety and Efficacy CoEE works to prevent adverse drug effects (ADEs) and to improve drug safety. The Center was created in 2005 to study the effects of prescription and over-the-counter medications, particularly on children and the elderly. The CoEE also is focused on education and outreach to health care professionals and the general public through the Doris Levkoff Meddin Medication Safety Education Program. Charles L. Bennett, M.D., Ph.D., M.P.P., was recruited in 2010 as the endowed chair and the Josie M. Fletcher Professor of Pharmacy at the University of South Carolina (USC) campus of the South Carolina College of Pharmacy. His appointment is supported in part by Health Sciences South Carolina , the Centers of Economic Excellence Program and the Frank P. and Josie M. Fletcher Endowment.
About the South Carolina College of Pharmacy
The South Carolina College of Pharmacy (SCCP) was formed in 2004 through the integration of the Colleges of Pharmacy at the University of South Carolina in Columbia (USC) and the Medical University of South Carolina in Charleston (MUSC). The SCCP is a statewide education, research, and service institution that combines the nationally recognized faculty, staff, and resources of MUSC, a major academic medical center, and USC, a large comprehensive university, to create a statewide approach to pharmacy education that is on a par with some of the most highly regarded colleges in the United States.